IGFBP‐2 expression in a human cell line is associated with increased IGFBP‐3 proteolysis, decreased IGFBP‐1 expression and increased tumorigenicity

Insulin‐like growth factors (IGF‐I and ‐II) play an active role in cell proliferation. In biological fluids, they are non‐covalently bound to high‐affinity binding proteins (IGFBPs), at least 6 species of which have been identified to date, but with poorly defined functions. One of these IGFBPs, IGFBP‐2, is secreted by most cell lines and appears to be involved in cell proliferation. A human epidermoid carcinoma cell line, KB 3.1, which produces IGFBP‐1 and ‐3 and small amounts of IGFBP‐4, but no IGFBP‐2, was stably transfected with an expression vector comprising IGFBP‐2 complementary DNA (cDNA), whose expression was placed under the control of the constitutive and ubiquitous cytomegalovirus promoter. After an s.c. injection of these IGFBP‐2‐expressing KB 3.1 cells into nude mice, tumours developed more quickly than in controls, they were 3 to 4 times larger and grew about 3 times as fast. Concomitant with IGFBP‐2 expression in these tumours, were a decrease in IGFBP‐1 expression and an increase in IGFBP‐3 proteolysis, both of which increase the bioavailability of the IGF‐II produced by the cells. The increased IGFBP‐3 proteolysis most probably resulted from amplified expression of tissue‐type plasminogen activator (t‐PA) and depression of its inhibitor (PAI‐1) observed in IGFBP‐2‐expressing xenografts. Our findings suggest that IGFBP‐2 plays a role in this model of experimental tumorigenesis via a mechanism that remains unclear, but appears to involve increased protease activity and IGF‐II bioavailability. Int. J. Cancer 77:874‐879, 1998.© 1998 Wiley‐Liss, Inc.